Phenylnorstatine of the formula (14) ##STR4## includes four optically active isomers. Among them, the one that can serve as a bestatin intermediate is the (2S,3R)-threo form and the one that can serve as a constituent of KNI- 227 is the (2S,3S)-erythro form. Therefore, a technique of selectively producing only one optical isomer is required for the production of such forms:by a commercially valuable method.
Several methods are known for the stereoselective production of the bestatin intermediate (2S,3R)-phenyl norstatin. Typical of them are those processes that comprise stereoselective addition of a cyanide compound to an (R)-2-amino-3-phenylpropanal derivative derived from D-phenylalanine [Journal of the Chemical Society Chemical Communications, 938 (1989); Synthesis, 703 (1989); European Patent Specification No. 341462; Japanese Kokai Publication Hei-2-17165]. From the industrial viewpoint, however, these processes pose a problem in that the use of a highly toxic cyanide compound is inevitable.
Other methods known include the process comprising degradation of an optically active 2-azetidone derivative obtained via [2+2] cycloaddition of a chiral imine and a ketene compound [Tetrahedron Letters, 31, 3031 (1990)], and the process comprising stereoselective alkylation and stereoselective amination of a chiral glyoxylate [Journal of Organic Chemistry, 54, 4235 (1989)]. However, these methods involve a number of steps, hence are complicated from the procedural viewpoint.
Further methods known comprise stereoselectively alkylating a malic acid ester, selectively amidating one of the carboxyl groups and subjecting the amidation product to Curtius type rearrangement to give optically active phenylnorstatine [European Patent Specification No. 379288; Tetrahedron Letters, 33, 6803 (1992)]. These methods, however, use lithium hexamethyldisilazane, which is an expensive base, and a toxic lead compound, among others, hence are not suited for commercial production.
On the other hand, few methods are known for the stereoselective production of (2S,3S)-phenylnorstatine derivatives. A technique is known which comprises erythro-selective addition of trimethylsilylcyanide to (S)-2-dibenzylamino-3-phenylpropanal in the presence of a Lewis acid [Tetrahedron Letters, 29, 3295 (1988)]. It appears possible to synthesize (2S,3S)-phenylnorstatine by applying this technique. However, the use of a toxic cyanide compound is inevitable in this case, too, and it is difficult to deprotect the dibenzyl protective group.
Another conceivable process making use of the above-mentioned method of selectively synthesizing (2S,3R)-phenylnorstatine derivatives might comprise selectively synthesizing the (2R,3S) form and inverting the configuration of the position 2 by tile per se known method [Journal of the American Chemical Society, 71, 110 (1949)] to give the (2S,3S) form. However, this process involves a large numbers of complicated procedural steps and therefore cannot be used commercially.
Furthermore, Japanese Kokai Publication Hei-2-59545 describes a method of producing 3-amino-4-cyclohexyl-1-nitro-2-butanol derivatives structurally similar to the compounds of the present invention, namely 3-amino-1-nitro-4-phenyl-2-butanol derivatives. However, the method described there is directed only to threo-selective synthesis and the reaction selectivity is as low as 1:1 to 2:1, rendering the method unsatisfactory.